JP2008290989A - Pharmaceutical comprising acid addition salt of dihydropyridine derivative - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an excellent pharmaceutical for therapy or prophylaxis of hypertension etc. <P>SOLUTION: A specific acid addition salt of 2-amino-1,4-dihydro-6-methyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid 3-(1-diphenylmethylazetidin-3-yl) ester 5-isopropyl ester is useful as the pharmaceutical for the therapy or the prophylaxis of the hypertension etc. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

The present invention provides an excellent calcium antagonistic action, blood pressure lowering action, vasodilatory action, cardioprotective action, anti-arteriosclerotic action, diuretic action, renal disorder inhibitory action, and lipid peroxide production inhibitory action. 1,4-Dihydro-6-methyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 3- (1-diphenylmethylazetidin-3-yl) ester Specific acid addition of 5-isopropyl ester salt;
2-amino-1,4-dihydro-6-methyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 3- (1-diphenylmethylazetidin-3-yl) ester 5-isopropyl ester Pharmaceutical composition containing a specific acid addition salt as an active ingredient, preferably a pharmaceutical composition for the treatment or prevention of hypertension, heart disease, arteriosclerosis, or renal disorder, more preferably hypertension Or a pharmaceutical composition for the treatment or prevention of heart disease, most preferably a pharmaceutical composition for the treatment or prevention of hypertension;
2-amino-1,4-dihydro-6-methyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 3- (1-diphenylmethylazetidin-3-yl) ester 5-isopropyl ester Diseases caused by administration of a pharmacologically effective amount of a specific acid addition salt to a warm-blooded animal (preferably a human), preferably hypertension, heart disease, arteriosclerosis, or renal disorder A method for the treatment or prevention of hypertension or heart disease, most preferably hypertension; and
2-amino-1,4-dihydro-6-methyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 3- (1-diphenylmethylazetidin-3-yl) ester 5-isopropyl ester The present invention relates to a method for producing a specific acid addition salt.

  2-amino-1,4-dihydro-6-methyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 3- (1-diphenylmethylazetidin-3-yl) which is a dihydropyridine calcium antagonist ) Ester 5-isopropyl ester [hereinafter also referred to as compound (I)] has pharmacological activities such as calcium antagonistic action and blood pressure lowering action, and is known to be useful as a medicament for the treatment of hypertension and the like. (See Patent Document 1 or 2). It is also known that a compound having a calcium antagonistic action is useful as a therapeutic agent for heart disease, arteriosclerosis, or renal disorder [eg, (i) Goodman & Gilman's The pharmacological basis of therapeutics, 32nd Chapter, p.767-774; (ii) Annual Report of Sankyo Research Laboratories, 2002, Vol. 54, p.1-64; (iii) The American Journal of Medicine, 1989, Vol. 86 (suppl 4A) , P.27-32; (iv) The American Journal of Hypertention, 1993, Vol. 6, p.251S-259S].

  As the acid addition salt of compound (I), dihydrochloride of compound (I) is known (see Patent Document 1 or 2), but other acid addition salts are not known. The dihydrochloride is produced by a method using hydrochloric acid gas and is an amorphous solid. So far, there is no known acid addition salt of Compound (I) that can be obtained as a crystalline solid.

It is useful to find a compound having superior properties in terms of solubility, oral absorbability, blood concentration, bioavailability (BA) and the like as compared with the free compound (I). Further, from the viewpoint of supplying a pharmaceutical compound having a certain quality on an industrial scale, it is useful to find an acid addition salt of compound (I) that can be obtained as a crystalline solid.
Japanese Patent Publication No. 3-31715 US Pat. No. 4,772,596

The present inventors have conducted intensive research on the acid addition salt of Compound (I), and the specific acid addition salt of Compound (I) exhibits excellent calcium antagonism, blood pressure lowering action, etc., and bioavailability Since it has excellent properties as a pharmaceutical compound in terms of crystallinity, thermal stability, etc., it has been found that it is useful as a pharmaceutical, particularly as a pharmaceutical for the treatment or prevention of hypertension, etc. completed.

The present invention provides an excellent calcium antagonistic action, blood pressure lowering action, vasodilatory action, cardioprotective action, anti-arteriosclerotic action, diuretic action, renal disorder inhibitory action, and lipid peroxide production inhibitory action. 1,4-Dihydro-6-methyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 3- (1-diphenylmethylazetidin-3-yl) ester Specific acid addition of 5-isopropyl ester salt;
2-amino-1,4-dihydro-6-methyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 3- (1-diphenylmethylazetidin-3-yl) ester 5-isopropyl ester Pharmaceutical composition containing a specific acid addition salt as an active ingredient, preferably a pharmaceutical composition for the treatment or prevention of hypertension, heart disease, arteriosclerosis, or renal disorder, more preferably hypertension Or a pharmaceutical composition for the treatment or prevention of heart disease, most preferably a pharmaceutical composition for the treatment or prevention of hypertension;
2-amino-1,4-dihydro-6-methyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 3- (1-diphenylmethylazetidin-3-yl) ester 5-isopropyl ester Diseases caused by administration of a pharmacologically effective amount of a specific acid addition salt to a warm-blooded animal (preferably a human), preferably hypertension, heart disease, arteriosclerosis, or renal disorder A method for the treatment or prevention of hypertension or heart disease, most preferably hypertension; and
2-amino-1,4-dihydro-6-methyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 3- (1-diphenylmethylazetidin-3-yl) ester 5-isopropyl ester A method for producing a specific acid addition salt is provided.

  The present invention is based on the following knowledge from one viewpoint.

  (I) Certain acid addition salts of compound (I) have superior pharmacokinetic properties (especially biochemistry) compared to the free form of compound (I) or other acid addition salts of compound (I). (Availability and blood concentration).

  Moreover, this invention is based on the following knowledge from another viewpoint.

  (Ii) Compound (I) forms an acid addition salt with a specific acid, but does not form an acid addition salt with other acids. That is, compound (I) has an excellent salt forming property with respect to a specific acid.

  (Iii) In the acid addition salt of compound (I) that can be obtained, the specific acid addition salt of compound (I) can be obtained as a crystalline solid, while the other acid addition salts can be obtained as an amorphous solid. Can only get. That is, the specific acid addition salt of compound (I) has excellent crystallinity as compared with other acid addition salts.

  (Iv) Among the acid addition salts of compound (I) that can be obtained, there is a difference in thermal stability depending on the type of acid addition salt. That is, the specific acid addition salt of compound (I) has excellent thermal stability compared to other acid addition salts.

  Furthermore, this invention is based on the following knowledge from another viewpoint.

  (V) Since compound (I) has two ester groups, it is usually expected that elimination of the ester residue by hydrolysis occurs in the presence of a strong acid and water. In addition, since acid addition salts are generally easily dissolved in water, it is usually expected that it is difficult to obtain acid addition salts in the presence of water. However, contrary to these expectations, the specific acid addition salt of compound (I) can be obtained in good yield as a crystalline solid under the reaction conditions in which a strong acid and water are present.

  The above findings (i) to (v) are all difficult to predict from the known prior art.

The present invention, from one point of view,
(1) 2-Amino-1,4-dihydro-6-methyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 3- (1-diphenylmethylazetidin-3-yl) ester 5- A pharmaceutical comprising an isopropyl ester hydrobromide, citrate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, or naphthalenesulfonate as an active ingredient,
(2) In (1), 2-amino-1,4-dihydro-6-methyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 3- (1-diphenylmethylazetidine-3- Yl) ester Pharmaceutical containing 5-isopropyl ester hydrobromide, methanesulfonate or p-toluenesulfonate as an active ingredient,
(3) In (2), 2-amino-1,4-dihydro-6-methyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 3- (1-diphenylmethylazetidine-3- Yl) ester A medicament containing 5-isopropyl ester hydrobromide as an active ingredient,
(4) In (3), 2-amino-1,4-dihydro-6-methyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 3- (1-diphenylmethylazetidine-3- Yl) ester A medicament containing 5-isopropyl ester dihydrobromide as an active ingredient,
(5) In (4), 2-amino-1,4-dihydro-6-methyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 3- (1-diphenylmethylazetidine-3- Yl) ester A medicament containing crystals of 5-isopropyl ester dihydrobromide as an active ingredient,
(6) In (5), in the powder X-ray diffractogram obtained by irradiation of copper Kα rays, the surface spacing is principally at 16, 4.4, 3.9, 3.1, and 3.0 angstroms. A drug containing a crystal showing a peak as an active ingredient,
(7) In (2), 2-amino-1,4-dihydro-6-methyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 3- (1-diphenylmethylazetidine-3- Yl) ester A medicament containing methanesulfonate of 5-isopropyl ester as an active ingredient,
(8) In (7), 2-amino-1,4-dihydro-6-methyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 3- (1-diphenylmethylazetidine-3- Yl) ester A pharmaceutical containing 5-isopropylester dimethanesulfonate as an active ingredient,
(9) In (8), 2-amino-1,4-dihydro-6-methyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 3- (1-diphenylmethylazetidine-3- Yl) ester A pharmaceutical containing crystals of 5-isopropyl ester dimethanesulfonate as an active ingredient,
(10) In the powder X-ray diffraction pattern obtained by irradiation with copper Kα rays in (9), the surface spacing is 12, 7.8, 6.1, 4.8, and 4.5 angstroms. A drug containing a crystal showing a peak as an active ingredient,
(11) In (7), 2-amino-1,4-dihydro-6-methyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 3- (1-diphenylmethylazetidine-3- Yl) ester A pharmaceutical containing trimethane sulfonate of 5-isopropyl ester as an active ingredient,
(12) In (11), 2-amino-1,4-dihydro-6-methyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 3- (1-diphenylmethylazetidine-3- Yl) ester A pharmaceutical comprising crystals of trimethanesulfonate of 5-isopropyl ester as an active ingredient,
(13) In the powder X-ray diffraction pattern obtained by irradiation with copper Kα rays in (12), the interplanar spacing is principally at 11, 4.6, 4.4, 3.9, and 3.6 angstroms. A drug containing a crystal showing a peak as an active ingredient,
(14) In (2), 2-amino-1,4-dihydro-6-methyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 3- (1-diphenylmethylazetidine-3- Yl) ester A medicament containing p-toluenesulfonate of 5-isopropyl ester as an active ingredient,
(15) In (14), 2-amino-1,4-dihydro-6-methyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 3- (1-diphenylmethylazetidine-3- Yl) ester A medicament containing 2-p-toluenesulfonate of 5-isopropyl ester as an active ingredient,
(16) In (15), 2-amino-1,4-dihydro-6-methyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 3- (1-diphenylmethylazetidine-3- Yl) ester A medicament containing a crystal of 2-p-toluenesulfonate of 5-isopropyl ester as an active ingredient,
(17) In the powder X-ray diffractogram obtained by irradiation with copper Kα rays in (16), the main peaks are at 6.8, 4.9, 4.7, and 4.2 angstroms. A medicine containing the crystals shown as an active ingredient,
(18) In any one of (1) to (17), a medicament for the treatment or prevention of hypertension, heart disease, arteriosclerosis, or renal disorder, or
(19) In (18), a medicament for treating or preventing hypertension is provided.

In the present invention, 2-amino-1,4-dihydro-6-methyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 3- (1-diphenylmethylazetidin-3-yl) ester 5 -Isopropyl ester is a compound having the following structural formula (Ia).

  In the present invention, the acid part of the acid addition salt of compound (I) is not particularly limited as long as it is an acid that can form an acid addition salt with compound (I). For example, hydrochloric acid, hydrobromic acid, hydrogen iodide Acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, oxalic acid, malonic acid, fumaric acid, maleic acid, tartaric acid, succinic acid, citric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, or naphthalenesulfonic acid Preferably, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, fumaric acid, tartaric acid, citric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, or naphthalenesulfonic acid, More preferably, it is hydrobromic acid, citric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, or naphthalenesulfonic acid, and more preferably water bromide. Acid, methanesulfonic acid, or a p- toluenesulfonic acid, even more preferably, hydrobromic acid or methanesulfonic acid, and most preferably a hydrobromide.

  In the present invention, compound (I) has three basic groups (amino group, azetidin-3-yl group, and dihydropyridyl group). In the acid addition salt formed from compound (I) and a monovalent, divalent or trivalent acid, the molar ratio of compound (I) and acid [compound (I) / acid] is In the case of a divalent acid, for example 2/1, 1/1 or 2/3, in the case of a trivalent acid, for example 3/1 It can be 3/2 or 1/1. The respective acid addition salts or mixtures thereof are encompassed by the present invention.

  In the present invention, the hydrobromide salt of compound (I) includes monohydrobromide salt, dihydrobromide salt and trihydrobromide salt, preferably dihydrobromide salt It is. The citrates of compound (I) include, for example, 1/3 tricitrate, 2/3 tricitrate and monocitrate, preferably monocitrate. The methanesulfonate of compound (I) includes monomethanesulfonate, dimethanesulfonate and trimethanesulfonate, preferably dimethanesulfonate or trimethanesulfonate, Most preferred is trimethanesulfonate. The benzene sulfonate of compound (I) includes monobenzene sulfonate, dibenzene sulfonate and tribenzene sulfonate, and is preferably dibenzene sulfonate. The p-toluene sulfonate of compound (I) includes mono-p-toluene sulfonate, di-p-toluene sulfonate and tri-p-toluene sulfonate, preferably di-p-toluene sulfonic acid Salt. The naphthalene sulfonate of the compound (I) includes mononaphthalene sulfonate, dinaphthalene sulfonate and trinaphthalene sulfonate, and is preferably dinaphthalene sulfonate.

In the present invention, the triacid salt is
(I) a salt formed from compound (I) (1 mol) in which three basic groups are protonated and an acid (3 mol) in which one proton is dissociated;
(Ii) a salt formed from a compound (I) (1 mol) in which two basic groups are protonated and an acid (2 mol) in which one proton is dissociated, and an acid in which no proton is dissociated An adduct formed from (1 mole); and
(Iii) a salt formed from a compound (I) (1 mol) in which one basic group is protonated and an acid (1 mol) in which one proton is dissociated, and an acid in which no proton is dissociated An adduct formed from (2 mol), preferably the salt shown in (i) above or the adduct shown in (ii) above, most preferably (ii) above. It is an adduct shown in. For example, the trimethanesulfonate salt of compound (I) is
(I-1) a salt formed from compound (I) (1 mol) in which three basic groups are protonated and methanesulfonate anion (MeSO ₃ ⁻ ) (3 mol);
(Ii-1) formed from a compound formed by protonation of two basic groups (I) (1 mol) and a methanesulfonate anion (2 mol), and methanesulfonic acid (1 mol) Adducts; and
(Iii-1) formed from a compound formed by protonating one basic group (I) (1 mol) and a methanesulfonate anion (1 mol), and methanesulfonic acid (2 mol) Preferably, it is a salt shown in (i-1) above or an adduct shown in (ii-1) above, and most preferably in (ii-1) above. Is the adduct shown.

  In the present invention, the acid addition salt of compound (I) can exist as a hydrate or a solvate, each of which or a mixture thereof is included in the present invention. In the present invention, hydrate includes hydrates containing any amount of water (eg, mono / dihydrate, monohydrate, dihydrate, etc.), and solvates are: Includes solvates containing any amount of solvent (eg, 1 / disolvate, monosolvate, disolvate, etc.).

  In the present invention, the acid addition salt of compound (I) has one asymmetric center, and optical isomers can exist, and each of these isomers and mixtures thereof can be represented by a single formula (Ia). It is described by the formula of The present invention encompasses each of these isomers and any mixture thereof (including racemates) in any proportion.

  In the present invention, the acid addition salt of compound (I) or a hydrate or solvate thereof is a crystal having a plurality of different internal structures and physicochemical properties (crystal polymorph) depending on reaction conditions and crystallization conditions. Each of these crystals or mixtures of them in any proportion are encompassed by the present invention. Moreover, although a crystalline solid and an amorphous (amorphous) solid may coexist, arbitrary ratios of those mixtures are included in the present invention. That is, the crystal having a specific crystal form of the present invention may contain a crystal having another crystal form or an amorphous solid, and the content of the specific crystal form is preferably 50% or more. More preferably, it is 80% or more, more preferably 90% or more, still more preferably 93% or more, particularly preferably 95% or more, and most preferably Is 97% or more.

  In the present invention, a crystal refers to a solid whose internal structure consists of a regular repetition of three-dimensional constituent atoms (or a group thereof), and is distinguished from an amorphous solid that does not have such a regular internal structure. The Whether or not a certain solid is a crystal can be examined by a crystallographically well-known method (for example, powder X-ray crystal analysis, differential scanning calorimetry, etc.). For example, powder X-ray crystal analysis using X-rays obtained by irradiation with copper Kα rays is performed on a solid, and when a clear peak is observed in the X-ray diffraction pattern, the solid is determined to be a crystal. If no clear peak is observed, the solid is determined to be amorphous. If the peak can be read but the peak is not clear (for example, broad), the solid is determined to be a crystal with low crystallinity, and such a crystal with low crystallinity is also included in the present invention. Are included in the crystal.

  In powder X-ray crystallographic analysis using copper Kα rays, the sample is usually irradiated with copper Kα rays (Kα1 and Kα2 rays are not separated). The X-ray diffraction diagram can be obtained by analyzing the diffraction derived from the Kα ray, or can be obtained by analyzing only the diffraction derived from the Kα1 ray extracted from the diffraction derived from the Kα ray. In the present invention, the powder X-ray diffraction diagram obtained by irradiation with Kα rays is an X-ray diffraction diagram obtained by analyzing diffraction derived from Kα rays, and X obtained by analyzing diffraction derived from Kα1 rays. It is an X-ray diffraction diagram including a line diffraction diagram, and preferably obtained by analyzing diffraction derived from the Kα1 line.

  In the following powder X-ray diffraction diagrams of FIGS. 1 to 11, the vertical axis represents diffraction intensity [count / second (cps)], and the horizontal axis represents diffraction angle 2θ (degrees). Further, the surface interval d (angstrom) can be calculated as n = 1 in the equation 2dsin θ = nλ. In the above formula, the wavelength λ of the Kα line is 1.54 angstroms, and the wavelength λ of the Kα1 line is 1.541 angstroms. Since the position and relative intensity of the interplanar spacing d can vary somewhat depending on the measurement conditions and the like, even if the interplanar spacing d is slightly different, the crystal form is identical with reference to the entire spectrum pattern as appropriate. Sex should be certified.

  The crystal of the dihydrobromide salt of the compound (I) of the present invention has, for example, a powder X-ray diffraction diagram obtained by irradiation with copper Kα rays as shown in FIG. It may be a crystal that exhibits major peaks at 4.4, 3.9, 3.1, and 3.0 angstroms. Here, the main peak is a peak having a relative intensity of 30 or more when the intensity of a peak having an interplanar spacing d of 16 angstroms is defined as 100.

  The crystal of the dimethanesulfonic acid salt of the compound (I) of the present invention has an interplanar spacing d of 12, 7 in a powder X-ray diffraction diagram obtained by irradiation with copper Kα rays as shown in FIG. Crystals that show major peaks at .8, 6.1, 4.8, and 4.5 angstroms. Here, the main peak is a peak having a relative intensity of 55 or more when the intensity of a peak having a surface interval d of 12 angstroms is defined as 100.

  The crystal of the trimethanesulfonate salt of the compound (I) of the present invention has an interplanar spacing d of 11, 4 in a powder X-ray diffraction diagram obtained by irradiation with copper Kα rays as shown in FIG. It may be a crystal showing major peaks at .6, 4.4, 3.9, and 3.6 angstroms. Here, the main peak is a peak having a relative intensity of 25 or more when the intensity of a peak having an interplanar spacing d of 11 angstroms is defined as 100.

  The crystal of the 2-p-toluenesulfonate salt of the compound (I) of the present invention has an interplanar spacing d of 6 in the powder X-ray diffraction pattern obtained by irradiation with copper Kα rays as shown in FIG. Crystals showing major peaks at .8, 4.9, 4.7, and 4.2 angstroms. Here, the main peak is a peak having a relative intensity of 45 or more when the intensity of a peak having a surface interval d of 6.8 angstroms is defined as 100.

In the present invention, the heart disease includes angina. In addition, heart disease, arteriosclerosis or renal disorder includes heart disease, arteriosclerosis or renal disorder caused by hypertension, respectively, and hypertension results from heart disease, arteriosclerosis or renal disorder, respectively. Hypertension is included.

2-amino-1,4-dihydro-6-methyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 3- (1-diphenylmethylazetidin-3-yl) ester of the present invention 5- Certain acid addition salts of isopropyl ester have excellent calcium antagonism, blood pressure lowering action, vasodilatory action, cardioprotective action, anti-arteriosclerotic action, diuretic action, renal disorder inhibitory action, and lipid peroxide production inhibitory action. Physicochemical properties, thermal stability, storage and handling stability, residual solvent ratio, hygroscopicity, deliquescence, solubility, pharmacological properties, pharmacokinetic properties, oral absorption, blood Since it has excellent properties as a pharmaceutical compound in terms of concentration, bioavailability, pharmacokinetics, safety, and toxicity, it is preferably used as a medicament as a hypertension, heart disease, arteriosclerosis, or It is useful as a medicament for the treatment or prevention of disorders, more preferably as a medicament for the treatment or prevention of hypertension or heart disease, most preferably as a medicament for the treatment or prevention of hypertension . In addition, the specific acid addition salt of the compound (I) of the present invention may have an excellent property that the blood concentration does not vary greatly due to changes in gastric pH and is not easily affected by food. As a blood animal medicine, it is preferably useful as a human medicine.

In the present invention, the acid addition salt of compound (I) can be produced by the following method:
(Step 1) Compound (I) is dissolved in an inert solvent or a water-containing inert solvent, and an acid, an aqueous solution of an acid or an inert solvent solution is dropped into the solution.
(Step 2) stirring for a certain time under a constant temperature condition (preferably room temperature condition); and
(Step 3) The produced solid is collected by filtration and dried.
If necessary, one or more steps selected from the group consisting of the following steps may be performed before or after step 2:
(Step 4-1) adding seed crystals;
(Step 4-2) a part of the solvent is distilled off;
(Step 4-3) adding a poor solvent (an inert solvent that does not dissolve the acid addition salt); and
(Step 4-4) Precipitation of crystals is initiated or accelerated by applying mechanical stimulation such as ultrasonic stimulation or rubbing of the surface of the reaction vessel.
In steps 1 and 2, it is preferred that water is present or an acid hydrate is used. In Step 1, an acid aqueous solution is preferably added dropwise to an inert solvent solution of Compound (I).

  Compound (I) used in the above production method can be produced according to the method described in Example 1 of JP-B-3-31715 (US Pat. No. 4,772,596). As the compound (I), any of isolated and purified compounds, solid reaction crude products, and solutions of reaction crude products can be used.

  The inert solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, aliphatic hydrocarbons such as hexane, pentane, petroleum ether, cyclohexane; benzene, toluene Aromatic hydrocarbons such as xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, dichlorobenzene; diethyl ether, diisopropyl ether, dibutyl ether, butyl methyl ether, sec- Ethers such as butyl methyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; like acetone, methyl ethyl ketone, methyl isobutyl ketone, cyclohexanone Ketones; esters such as ethyl acetate, propyl acetate and butyl acetate; nitriles such as acetonitrile, propionitrile, butyronitrile and isobutyronitrile; methanol, ethanol, 1-propanol, 2-propanol, 1- Alcohols such as butanol, 2-butanol, 2-methyl-1-propanol, 2-methyl-2-propanol; such as formamide, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone, hexamethylphosphorotriamide Amides; water; or a mixture thereof, preferably aromatic hydrocarbons, ethers, ketones, esters, alcohols, water, or a mixture thereof, more preferably Is toluene, tert-butyl methyl ether, acetone , Ethyl acetate, methanol, ethanol, 1-propanol, 2-propanol, or a mixture of these solvents and water, more preferably toluene, acetone, ethyl acetate, methanol, ethanol, or these solvents. It is a mixture of water. The inert solvent used in the preparation of the dihydrobromide salt of compound (I) is preferably acetone, ethyl acetate, methanol, ethanol, or a mixture of these solvents and water, more preferably Is acetone, methanol, or a mixture of these solvents and water, most preferably methanol or a mixture of methanol and water. The inert solvent used in the production of the trimethanesulfonate of compound (I) is preferably toluene or ethyl acetate, and most preferably ethyl acetate. It is also preferable that an appropriate amount of water is present in the reaction solution.

  When the acid used is a monovalent acid, the amount of the acid used may be, for example, 0.4 to 10 mol, preferably 0.6 to 1 mol (mol) of the compound (I). It is thru | or 6 mol, More preferably, it is 0.8 to 5 mol.

  When the acid used is a divalent acid, the amount of acid used can be, for example, 0.2 to 10 mol, preferably 0.3 to 6 mol, relative to 1 mol of compound (I). More preferably, it is 0.4 to 4 mol.

  When the acid used is a trivalent acid, the amount of acid used can be, for example, 0.1 to 10 mol, preferably 0.2 to 6 mol, relative to 1 mol of compound (I). And more preferably 0.3 to 4 moles.

  The concentration of the aqueous acid solution or inert solvent solution used can be, for example, from 0.1 mol / liter (mol / l) to a saturated solution, preferably from 1 to 20 mol / liter, More preferably, it is 3 to 15 mol / liter.

  The reaction temperature is usually −20 ° C. to 150 ° C., preferably 0 ° C. to 100 ° C., more preferably 10 ° C. to 60 ° C.

  While the reaction time varies depending on the acid, solvent, reaction temperature, etc. used, it is usually 5 minutes to 24 hours, preferably 10 minutes to 12 hours, more preferably 20 minutes to 6 hours.

  The resulting solid can be isolated, for example, by filtration, centrifugation, or gradient methods. The isolated solid can be washed with an inert solvent (preferably the inert solvent used in the reaction), if necessary.

  The isolated solid is usually dried at 20 to 80 ° C., preferably 30 to 60 ° C. under reduced pressure. The drying time is usually the time until the weight does not substantially change, but is preferably 30 minutes to 12 hours, and more preferably 1 to 6 hours. If necessary, the solid can be dried in the presence of a desiccant such as silica gel and / or calcium chloride.

  The reaction conditions are preferably conditions that do not cause hydrolysis reaction of two ester groups of compound (I).

  When the acid addition salt of the compound (I) of the present invention is used as a medicine, it can be administered as it is (as it is), or an appropriate pharmacologically acceptable excipient, As a preparation such as tablets, capsules, granules, powders or syrups manufactured by mixing with diluents, etc., or as a preparation such as injections or suppositories manufactured similarly, It can be administered orally (preferably orally).

  These preparations are produced by well-known methods using additives such as excipients, lubricants, binders, disintegrants, emulsifiers, stabilizers, flavoring agents, and / or diluents.

  The excipient can be, for example, an organic excipient or an inorganic excipient. Organic excipients include, for example, sugar derivatives such as lactose, sucrose, glucose, mannitol, sorbitol; starch derivatives such as corn starch, potato starch, α-starch, dextrin; cellulose derivatives such as crystalline cellulose; It can be gum arabic; dextran; or pullulan. The inorganic excipient can be, for example, light anhydrous silicic acid; or a sulfate such as calcium sulfate.

  Lubricants include, for example, stearic acid; metal stearates such as calcium stearate and magnesium stearate; talc; colloidal silica; waxes such as beeswax and gay wax; boric acid; adipic acid; Sulfate; glycol; fumaric acid; sodium benzoate; D, L-leucine; lauryl sulfate such as sodium lauryl sulfate and magnesium lauryl sulfate; silicic acids such as anhydrous silicic acid and silicic acid hydrate; or the above-mentioned shaping It can be a starch derivative in the agent.

  The binder can be, for example, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyethylene glycol, or a compound indicated by the excipients described above.

  Disintegrants include, for example, low substituted hydroxypropylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium, cellulose derivatives such as internally crosslinked sodium carboxymethylcellulose; crosslinked polyvinylpyrrolidone; or chemical modifications such as carboxymethyl starch, carboxymethyl starch sodium Starch / celluloses.

  The emulsifier may be, for example, a colloidal clay such as bentonite or bee gum; an anionic surfactant such as sodium lauryl sulfate or calcium stearate; a cationic surfactant such as benzalkonium chloride; or a polyoxyethylene alkyl ether And non-ionic surfactants such as polyoxyethylene sorbitan fatty acid ester and sucrose fatty acid ester.

  Stabilizers include, for example, parahydroxybenzoates such as methylparaben and propylparaben; alcohols such as chlorobutanol, benzyl alcohol and phenylethyl alcohol; benzalkonium chloride; phenols such as phenol and cresol; thimerosal Dehydroacetic acid; or sorbic acid.

  The flavoring agent can be, for example, a sweetener such as sodium saccharin or aspartame; an acidulant such as citric acid, malic acid or tartaric acid; or a flavor such as menthol, lemon extract or orange extract.

  The diluent may be a compound that is usually used as a diluent, such as lactose, mannitol, glucose, sucrose, calcium sulfate, hydroxypropylcellulose, microcrystalline cellulose, water, ethanol, polyethylene glycol, propylene glycol, glycerol, It can be starch, polyvinylpyrrolidone, or a mixture thereof.

The dose of the acid addition salt of the compound (I) of the present invention may vary depending on conditions such as patient's symptoms, age, body weight, etc., but in the case of oral administration, the lower limit is 0.005 mg / kg per dose. (Preferably 0.02 mg / kg), upper limit 20 mg / kg (preferably 10 mg / kg), and for parenteral administration, lower limit 0.0005 mg / kg per dose (preferably 0.002 mg / kg) and an upper limit of 20 mg / kg (preferably 10 mg / kg) can be administered to adults 1 to 6 times per day depending on the symptoms.

  Hereinafter, the present invention will be described in more detail with reference to Examples, Comparative Examples, Test Examples, and Formulation Examples, but the scope of the present invention is not limited thereto. In the following examples, 2-amino-1,4-dihydro-6-methyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 3- (1-diphenylmethylazetidin-3-yl) Ester 5-isopropyl ester can be produced according to the method described in Example 1 of JP-B-3-31715 (US Pat. No. 4,772,596).

Example 1 2-Amino-1,4-dihydro-6-methyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 3- (1-diphenylmethylazetidin-3-yl) ester 5-Isopropyl ester dihydrobromide 2-amino-1,4-dihydro-6-methyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 3- (1-diphenylmethylazetidine- 3-yl) ester To a solution of 2.91 g (5.00 mmol) of 5-isopropyl ester in 12 ml of methanol, 1.27 ml (11.0 mmol) of 47 wt% hydrobromic acid was added dropwise at 25 ° C. over 30 minutes. After completion of dropping, the reaction solution was further stirred for 30 minutes. The produced crude crystals were collected by filtration, washed with 12 ml of methanol, and dried under reduced pressure at 50 ° C. for 2 hours to obtain 2.90 g (78%) of the title compound as a white powder.
¹ H-NMR spectrum (DMSO-d ₆ , δ ppm): 1.00 (d; J = 6 Hz, 3H), 1.19 (d; J = 6 Hz, 3H), 2.29 (s, 3H), 4.01-4.38 (m, 4H ), 4.74-4.92 (m, 2H), 4.96-5.23 (m, 1H), 5.78-6.11 (m, 1H), 6.85 (brs, 2H), 7.37-7.77 (m, 12H), 7.94-8.09 (m , 2H), 8.98 (brs, 1H), 11.17-11.77 (m, 1H).

  The powder X-ray diffraction pattern of this compound is shown in FIG. This compound had a clear peak in the X-ray diffraction pattern and was a crystalline solid.

  This compound can also be produced using tert-butyl methyl ether, acetone, ethyl acetate, ethanol, 1-propanol, or 2-propanol as a solvent. The solvent used for the production of the present compound is preferably acetone, ethyl acetate, methanol, or ethanol, more preferably acetone or methanol, and most preferably methanol.

Example 2 2-Amino-1,4-dihydro-6-methyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 3- (1-diphenylmethylazetidin-3-yl) ester 5-isopropyl ester monocitrate 2-amino-1,4-dihydro-6-methyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 3- (1-diphenylmethylazetidine-3- Yl) ester To 11.1 ml of acetone in 3.24 g (5.56 mmol) of 5-isopropyl ester, 11.1 ml (5.83 mmol) of citric acid in 11.1 ml of acetone was added dropwise at 25 ° C. over 30 minutes. After completion of dropping, the reaction solution was further stirred for 40 minutes. The formed crude crystals were collected by filtration, washed with 5 ml of acetone, and dried under reduced pressure at 50 ° C. for 2 hours to obtain 3.42 g (79%) of the title compound as a yellow powder.
¹ H-NMR spectrum (DMSO-d ₆ , δ ppm): 0.99 (d; J = 6 Hz, 3H), 1.18 (d; J = 6 Hz, 3H), 2.27 (s, 3H), 2.30-2.42 (m, 1H ), 2.64 (d; J = 15Hz, 2H), 2.75 (d; J = 15Hz, 2H), 2.86-2.97 (m, 1H), 3.28-3.40 (m, 1H), 3.49-3.58 (m, 1H) , 4.21 (s, 1H), 4.72-4.91 (m, 3H), 6.75 (brs, 2H), 7.12-7.41 (m, 10H), 7.54-7.67 (m, 2H), 8.02-8.12 (m, 2H) , 8.80 (brs, 1H), 12.34 (brs, 1H).

  The powder X-ray diffraction pattern of this compound is shown in FIG. This compound had a clear peak in the X-ray diffraction pattern and was a crystalline solid.

Example 3 2-Amino-1,4-dihydro-6-methyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 3- (1-diphenylmethylazetidin-3-yl) ester 5-isopropyl ester dimethanesulfonate 2-amino-1,4-dihydro-6-methyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 3- (1-diphenylmethylazetidine-3 -Il) Ester To a solution of 4.66 g (8.00 mmol) of 5-isopropyl ester in 32 ml of ethyl acetate, 1.04 ml (16.0 mmol) of methanesulfonic acid was added dropwise at 25 ° C. over 30 minutes. After completion of dropping, the reaction solution was further stirred for 30 minutes. The formed crude crystals were collected by filtration, washed with 20 ml of ethyl acetate, and dried under reduced pressure at 40 ° C. for 2 hours to obtain 6.01 g (97%) of the title compound as a white powder.
¹ H-NMR spectrum (DMSO-d ₆ , δ ppm): 1.00 (d; J = 6 Hz, 3H), 1.18 (d; J = 6 Hz, 3H), 2.28 (s, 3H), 2.38 (s, 6H), 4.03-4.42 (m, 4H), 4.73-4.89 (m, 2H), 4.96-5.18 (m, 1H), 5.73-6.01 (m, 1H), 6.85 (brs, 2H), 7.37-7.67 (m, 12H ), 7.93-8.04 (m, 2H), 8.96 (brs, 1H), 11.01-11.42 (m, 1H).

  The powder X-ray diffraction pattern of this compound is shown in FIG. This compound had a clear peak in the X-ray diffraction pattern and was a crystalline solid.

  This compound can also be produced using tert-butyl methyl ether, methanol, ethanol, or 2-propanol as a solvent.

Example 4 2-Amino-1,4-dihydro-6-methyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 3- (1-diphenylmethylazetidin-3-yl) ester 5-isopropyl ester trimethanesulfonate 2-amino-1,4-dihydro-6-methyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 3- (1-diphenylmethylazetidine-3 -Yl) ester To a solution of 4.66 g (8.00 mmol) of 5-isopropyl ester in 32 ml of ethyl acetate, 1.71 ml (26.4 mmol) of methanesulfonic acid was added dropwise at 25 ° C. over 30 minutes. After completion of dropping, the reaction solution was further stirred for 30 minutes. The produced crude crystals were collected by filtration, washed with 20 ml of ethyl acetate, and dried under reduced pressure at 40 ° C. for 2 hours to obtain 6.78 g (97%) of the title compound as a white powder.
¹ H-NMR spectrum (DMSO-d ₆ , δ ppm): 1.00 (d; J = 6 Hz, 3H), 1.19 (d; J = 6 Hz, 3H), 2.28 (s, 3H), 2.40 (s, 9H), 4.02-4.42 (m, 4H), 4.75-4.88 (m, 2H), 4.98-5.18 (m, 1H), 5.73-6.10 (m, 1H), 6.84 (brs, 2H), 7.35-7.69 (m, 12H ), 7.91-8.07 (m, 2H), 8.97 (brs, 1H), 11.01-11.45 (m, 1H).

  The powder X-ray diffraction pattern of this compound is shown in FIG. This compound had a clear peak in the X-ray diffraction pattern and was a crystalline solid.

  This compound can also be produced using toluene as a solvent.

Example 5 2-Amino-1,4-dihydro-6-methyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 3- (1-diphenylmethylazetidin-3-yl) ester 5-isopropyl ester dibenzenesulfonate 2-amino-1,4-dihydro-6-methyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 3- (1-diphenylmethylazetidine-3 -Yl) ester To a solution of 4.66 g (8.00 mmol) of 5-isopropyl ester in 32 ml of ethyl acetate, at 25 ° C., a solution of 4.23 g (24.0 mmol) of benzenesulfonic acid monohydrate in 15 ml of ethyl acetate was added for 30 minutes. It was dripped at. After completion of dropping, the reaction solution was further stirred for 30 minutes. The formed crude crystals were collected by filtration, washed with 20 ml of ethyl acetate, and dried under reduced pressure at 40 ° C. for 2 hours to obtain 7.13 g (99%) of the title compound as a white powder.
¹ H-NMR spectrum (DMSO-d ₆ , δ ppm): 1.00 (d; J = 6 Hz, 3H), 1.19 (dd; J = 6 Hz, 2 Hz, 3H), 2.28 (s, 3H), 3.98-4.44 (m , 4H), 4.72-4.96 (m, 2H), 4.94-5.18 (m, 1H), 5.72-6.00 (m, 1H), 6.84 (brs, 2H), 7.26-7.67 (m, 22H), 7.93-8.03 (m, 2H), 8.92 (brs, 1H), 10.88-11.38 (m, 1H).

  The powder X-ray diffraction pattern of this compound is shown in FIG. This compound had a clear peak in the X-ray diffraction pattern and was a crystalline solid.

Example 6 2-Amino-1,4-dihydro-6-methyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 3- (1-diphenylmethylazetidin-3-yl) ester 5-Isopropyl ester 2-p-toluenesulfonate 2-amino-1,4-dihydro-6-methyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 3- (1-diphenylmethylazetidine -3-yl) ester To a solution of 4.66 g (8.00 mmol) of 5-isopropyl ester in 32 ml of ethyl acetate at 25 ° C., 4.57 g (24.0 mmol) of p-toluenesulfonic acid monohydrate in 20 ml of ethyl acetate The solution was added dropwise over 30 minutes. After completion of dropping, the reaction solution was further stirred for 30 minutes. The formed crude crystals were collected by filtration, washed with 20 ml of ethyl acetate, and dried under reduced pressure at 40 ° C. for 2 hours to obtain 7.65 g (quantitative) of the title compound as a white powder.
¹ H-NMR spectrum (DMSO-d ₆ , δ ppm): 1.00 (d; J = 6 Hz, 3H), 1.18 (dd; J = 6 Hz, 2 Hz, 3H), 2.28 (s, 3H), 2.29 (s, 6H ), 4.08-4.43 (m, 4H), 4.73-4.90 (m, 2H), 4.96-5.19 (m, 1H), 5.74-6.00 (m, 1H), 6.85 (brs, 2H), 7.10-7.16 (m , 4H), 7.38-7.66 (m, 16H), 7.94-8.05 (m, 2H), 8.92 (brs, 1H), 10.93-11.42 (m, 1H).

  The powder X-ray diffraction pattern of this compound is shown in FIG. This compound had a clear peak in the X-ray diffraction pattern and was a crystalline solid.

Example 7 2-Amino-1,4-dihydro-6-methyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 3- (1-diphenylmethylazetidin-3-yl) ester 5-isopropyl ester dinaphthalenesulfonate 2-amino-1,4-dihydro-6-methyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 3- (1-diphenylmethylazetidine-3 -Yl) ester To a solution of 4.66 g (8.00 mmol) of 5-isopropyl ester in 32 ml of ethyl acetate, at 25 ° C., a solution of 5.97 g (26.4 mmol) of 2-naphthalenesulfonic acid monohydrate in 120 ml of ethyl acetate. It was dripped in 30 minutes. After completion of dropping, the reaction solution was further stirred for 30 minutes. The reaction solution was allowed to stand at 2 ° C. for 4 days to precipitate a solid. The precipitated crude solid was collected by filtration, washed with 100 ml of ethyl acetate, and dried under reduced pressure at 45 ° C. for 3 hours to obtain 7.72 g (97%) of the title compound as a white powder.
¹ H-NMR spectrum (DMSO-d ₆ , δppm): 1.00 (d; J = 6 Hz, 3H), 1.18 (dd; J = 6 Hz, 2 Hz, 3H), 2.28 (s, 3H), 4.06-4.42 (m , 4H), 4.74-4.90 (m, 2H), 4.96-5.18 (m, 1H), 5.73-6.00 (m, 1H), 6.84 (brs, 2H), 7.37-7.57 (m, 15H), 7.60-7.66 (m, 1H), 7.70-7.76 (m, 2H), 7.85-8.04 (m, 8H), 8.14-8.18 (m, 2H), 8.92 (brs, 1H), 10.88-11.37 (m, 1H).

  The powder X-ray diffraction pattern of this compound is shown in FIG. This compound had a clear peak in the X-ray diffraction pattern and was a crystalline solid.

Comparative Example 1 2-Amino-1,4-dihydro-6-methyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 3- (1-diphenylmethylazetidin-3-yl) ester 5-Isopropyl ester dihydrochloride (aqueous solution method)
2-Amino-1,4-dihydro-6-methyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 3- (1-diphenylmethylazetidin-3-yl) ester 5-isopropyl ester 4 36 wt% hydrochloric acid 1.49 ml (17.6 mmol) was added dropwise to a solution of .66 g (8.00 mmol) in ethyl acetate 32 ml at 25 ° C. over 30 minutes. After completion of dropping, the reaction solution was further stirred for 30 minutes. The produced crude crystals were collected by filtration, washed with 10 ml of ethyl acetate, and dried under reduced pressure at 50 ° C. for 1 hour to obtain 5.26 g (92%) of the title compound as a white powder.
¹ H-NMR spectrum (DMSO-d ₆ , δ ppm): 0.99 (d; J = 6 Hz, 3H), 1.19 (dd; J = 6 Hz, 3 Hz, 3H), 2.29 (s, 3H), 3.90-4.28 (m , 4H), 4.70-5.32 (m, 3H), 5.68-6.03 (m, 1H), 6.93 (brs, 2H), 7.32-7.77 (m, 12H), 7.91-8.06 (m, 2H), 9.21-9.38 (m, 1H), 12.58-12.91 (m, 1H).

  The powder X-ray diffraction pattern of this compound is shown in FIG. The compound obtained by the aqueous solution method had a clear peak in the X-ray diffraction pattern and was a crystalline solid.

Comparative Example 2 2-Amino-1,4-dihydro-6-methyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 3- (1-diphenylmethylazetidin-3-yl) ester 5-Isopropyl ester dihydrochloride (gas method)
According to the method described in Example 1 of JP-B-3-31715 (US Pat. No. 4,772,596), the title compound was produced as follows.

  2-Amino-1,4-dihydro-6-methyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 3- (1-diphenylmethylazetidin-3-yl) ester 5-isopropyl ester 2 A solution of .91 g (5.00 mmol) in 66.7 ml of chloroform was stirred at 25 ° C. while blowing hydrogen chloride gas for 5 minutes. The reaction solution was concentrated under reduced pressure, and the resulting solid was dried under reduced pressure at 50 ° C. for 2 hours to give 3.65 g (quantitative) of the title compound as a pale yellow solid.

The ¹ H-NMR spectrum of this compound was the same as that of the compound of Comparative Example 1.

  The powder X-ray diffraction pattern of this compound is shown in FIG. This compound obtained by the gas method did not have a clear peak in the X-ray diffraction pattern, and was an amorphous solid.

  From the results of Comparative Examples 1 and 2, it was shown that a production method using an aqueous acid solution was useful for obtaining an acid addition salt of the crystalline compound (I).

Comparative Example 3 2-Amino-1,4-dihydro-6-methyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 3- (1-diphenylmethylazetidin-3-yl) ester 5-isopropyl ester monosulfate 2-amino-1,4-dihydro-6-methyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 3- (1-diphenylmethylazetidin-3-yl) ) Ester To a solution of 5.99 g (12.0 mmol) of 5-isopropyl ester in 24 ml of acetone, 0.70 ml (12.6 mmol) of 96% sulfuric acid was added dropwise at 25 ° C. over 30 minutes. After completion of dropping, the reaction solution was further stirred for 20 minutes. The resulting yellow viscous solid was allowed to stand for 2 hours, and then the solidified solid was washed with 30 ml of acetone and dried under reduced pressure at 45 ° C. for 2 hours to give 7.55 g (92%) of the title compound as a pale yellow powder. Got as.
¹ H-NMR spectrum (DMSO-d ₆ , δ ppm): 1.00 (d; J = 6 Hz, 3H), 1.18 (d; J = 6 Hz, 3H), 2.28 (s, 3H), 4.00-4.43 (m, 4H ), 4.72-4.90 (m, 2H), 4.96-5.18 (m, 1H), 5.64-6.02 (m, 1H), 6.85 (brs, 2H), 7.33-7.70 (m, 12H), 7.92-8.08 (m , 2H), 8.93 (brs, 1H), 10.93-11.41 (m, 1H).

  The powder X-ray diffraction pattern of this compound is shown in FIG. This compound had a clear peak in the X-ray diffraction pattern and was a crystalline solid. However, in the above production process, it is necessary to leave the yellow viscous solid to solidify in order to form crystals, and this compound is crystallized compared to the specific acid addition salt of the compound (I) of the present invention. The sex was low.

Comparative Example 4 2-Amino-1,4-dihydro-6-methyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 3- (1-diphenylmethylazetidin-3-yl) ester 5-isopropyl ester 1 / difumarate 2-amino-1,4-dihydro-6-methyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 3- (1-diphenylmethylazetidine- 3-yl) ester To a solution of 5-isopropyl ester (5.00 g, 8.58 mmol) in ethyl acetate (15 ml) at 25 ° C., fumaric acid (997 mg, 8.59 mmol) in tetrahydrofuran (24 ml) was added dropwise over 35 minutes. After completion of the dropwise addition, the reaction solution was further stirred for 15 minutes, and 78 ml of diisopropyl ether was added. The produced solid was collected by filtration, washed with 5 ml of ethyl acetate, and dried under reduced pressure at 45 ° C. for 2 hours to obtain 5.14 g (93%) of the title compound as a yellow powder.
¹ H-NMR spectrum (DMSO-d ₆ , δ ppm): 0.99 (d; J = 6 Hz, 3H), 1.18 (d; J = 6 Hz, 3H), 2.22-2.39 (m, 4H), 2.85-2.92 (m , 1H), 3.22-3.50 (m, 2H), 4.18 (s, 1H), 4.72-4.91 (m, 3H), 6.63 (s, 1H), 6.77 (brs, 2H), 7.13-7.41 (m, 10H ), 7.55-7.66 (m, 2H), 8.03-8.12 (m, 2H), 8.83 (brs, 1H), 13.12 (brs, 1H).

  The powder X-ray diffraction pattern of this compound is shown in FIG. This compound had a clear peak in the X-ray diffraction pattern and was a crystalline solid. However, in the above production process, it is necessary to add a poor solvent (diisopropyl ether) in order to form crystals, and this compound is crystalline compared to the specific acid addition salt of compound (I) of the present invention. Was low.

(Test Example 1) Thermal stability test A test compound is placed in a glass bottle and allowed to stand under the following conditions (1) and (2). After a certain period of time, the active ingredient in the test compound [Compound (I) ] Was measured by high performance liquid chromatography.

(1): Sealed state, 60 ° C .;
(2): Non-sealed state, 40 ° C., humidity 75%.

  The measurement conditions for high performance liquid chromatography are as follows.

Column: L-column ODS [4.6mm × 250mm, manufactured by Chemical Substance Evaluation Research Organization]
Moving bed: acetonitrile / 22 mM potassium dihydrogen phosphate buffer / methanol = 455/350/195 (V / V / V) (adjusted to pH 5.5 with phosphoric acid)
Flow rate: 1ml / min
Column temperature: 40 ° C
Detection wavelength: 220 nm
The residual rate (%) was calculated by the following formula.

Residual rate (%) = [1− (sum of peak area percentage of impurities and decomposition products)] × 100
The results under the above conditions (1) and (2) are shown in Tables 1 and 2, respectively.

[Table 1] [Condition (1)]
______________________________________________
Test compound Residual rate of compound (I) (%)
Number Time (Month): 0 1 3 6
￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣
Example 1 99.9 99.7 99.7 99.6
Example 2 98.8 96.9 95.8
Example 3 99.6 98.7 98.5
Example 4 99.5 98.6 98.1
Example 5 99.7 98.6 96.5 93.3
Example 6 99.6 98.8 98.3 97.3
Example 7 99.4 97.3 95.4 93.0
______________________________________________
Comparative Example 1 98.1 60.0 58.9
Comparative Example 2 97.3 10.3
Comparative Example 3 99.5 96.9 94.9 92.8
Comparative Example 4 99.7 96.7 93.0
______________________________________________

From the results shown in Table 1, the stability of the compound of Comparative Example 2 which is an amorphous solid was very low, and the stability of the compound of Comparative Example 1 was very low despite being a crystalline solid. Further, the compounds of Comparative Examples 3 and 4 were not highly stable although they were crystalline solids. In comparison, the compounds of Examples 1 to 7 of the present invention were crystalline solids and showed excellent stability. The compounds of Examples 2, 5 and 7 of the present invention were equivalent in stability to the compounds of Comparative Examples 3 and 4, but excellent in crystallinity (see Comparative Examples 3 and 4 above).

[Table 2] [Condition (2)]
______________________________________________
Test compound Residual rate of compound (I) (%)
Number Time (Month): 0 1 3 6
￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣
Example 1 99.9 99.5 99.1 98.9
Example 4 99.5 99.1 98.8
Example 6 99.6 97.5 96.4 94.5
______________________________________________
Comparative Example 1 98.1 62.9 59.0
Comparative Example 2 97.3 11.3
Comparative Example 3 99.5 93.9 88.9 84.8
Comparative Example 4 99.7 94.8 91.3
______________________________________________

From the results of Table 2, the stability of the compound of Comparative Example 2 which is an amorphous solid is very low, and the compounds of Comparative Examples 1, 3 and 4 have low stability despite being a crystalline solid. It was. In comparison, the compounds of Examples 1, 4 and 6 of the present invention were crystalline solids and showed excellent stability.

  The results in Tables 1 and 2 show that not all of the acid addition salts of Compound (I) that can be obtained as a crystalline solid have excellent thermal stability, and the specific acid addition of Compound (I) of the present invention It shows that the salt has excellent thermal stability compared to other acid addition salts.

(Test Example 2) Absorbency test in dogs (1) Method Male beagle dogs (weight: about 10 kg) fasted with tetragastrin (6 μg / kg) 30 minutes before, just before, and 30 minutes after administration of the test compound. n = 4) The intragastric pH was adjusted to be acidic by intramuscular injection into the hind leg thigh. The test compound was encapsulated in a gelatin capsule at a dose of 100 mg / body and orally administered. Approximately 0.5 ml of blood was collected from the forearm mesenteric vein using a heparin-treated syringe 0.5, 1, 2, 3, 4, 6, 8 and 24 hours after administration. The collected blood was centrifuged to obtain plasma and stored frozen at −20 ° C. until the concentration of the test compound was measured. Thawed plasma 100 [mu] l of 50% methanol 100 [mu] l, purified water 800 [mu] l, 0.1 N aqueous hydrochloric acid 100 [mu] l, and [solution compound d _7-body (I) was dissolved in 50% methanol, 50 ng / ml] Internal standard solution 100 [mu] l added The eluate obtained by solid phase extraction using OASIS HLB was evaporated to dryness and then dissolved in 400 μl of 75% methanol and analyzed by LC / MS / MS.

  The calibration curve was prepared in the same manner as described above using 100 μl of canine control plasma to which no drug was administered and 100 μl of a standard curve standard solution [solution of Compound (I) dissolved in 50% methanol, 0.1-1000 ng / ml] It was performed by operating.

The analysis conditions for LC / MS / MS are shown below.
[MS / MS]
System: API4000 LC / MS / MS System (Applied Biosystems / MDS SCIEX)
Ion source: TurboIonSpray
Turbo heater gas: Air, 650 ° C, 70 psi
Nebulizer gas: Air, 70 psi
Curtain gas: N ₂ , 40
Orifice voltage: Compound (I) 106 V
D ₇ form 106 V of compound (I)
Ion spray voltage: 5500 V
Collision gas: N ₂ , 3
Collision energy: Compound (I) 35 V
D ₇ compound 35 V of compound (I)
Measurement mode: positive / MRM
Monitor ion: Compound (I) m / z 583 → 167
D ( ₇ ) of compound (I) m / z 590 → 167
[HPLC]
System: Agilent 1100 Series (Agilent Technologies)
Column: Inertsil ODS-3 5 μm, 2.1 mm ID x 150 mm (GL Science)
Mobile phase: methanol / water / difluoroacetic acid (700/300 / 0.75)
Flow rate: 0.15 ml / min
Column temperature: 40 ° C
Injection volume: 5 μl
(2) Results Plasma concentration-time curve, which is a pharmacokinetic parameter serving as an index of drug absorbability, based on the results obtained according to the above method using the compound of Example 1 and Compound (I) as test compounds The lower area (AUC _0-24h ) and the maximum plasma concentration (Cmax) were calculated. The results are shown in Table 3.

[Table 3]
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Test compound number AUC _0-24h [ng · h / ml] Cmax [ng / ml]
￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣
Example 1 2933 248
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Compound (I) 1813 178
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The compound of Example 1 of the present invention showed excellent bioavailability and blood concentration (AUC _0-24h and Cmax) as compared with the free compound (I).

(Test Example 3) Dissolution test (1) Method One gelatin capsule (100 mg equivalent / capsule) filled with the test compound and the first disintegration test solution as the test solution (14th revised Japanese Pharmacopoeia, pH 1.2) Using 900 ml, the test was conducted under the condition of 250 revolutions per minute according to the dissolution test method No. 2 (14th revised Japanese Pharmacopoeia, paddle method). A sinker (14th revised Japanese Pharmacopoeia dissolution test method) was used to prevent gelatin capsules from floating. After 5, 10, 15, 20, 30, 45, 60, 75, 90, 105, and 120 minutes after starting the dissolution test, about 20 ml of the test solution was filtered with a 10 μm pore size filter (manufactured by VARIAN, Full Flow Filters 10 μm ), And sent directly into a flow cell (optical path length 0.5 cm) in the circulation system, and the absorbance was measured with a photodiode array type spectrophotometer (HP 8452A). The concentration of compound (I) in the test solution was measured by comparing the absorbance of compound (I) in the test solution at the time of collecting each test solution with the absorbance of the following standard solution.

  The standard solution was adjusted as follows. About 28 mg of Compound (I) was accurately weighed and added to a 500 ml volumetric flask. 5 ml of ethanol (99.5%, reagent grade) was added, and compound (I) was dissolved while applying ultrasonic stimulation as necessary. The first solution for disintegration test was added to make exactly 500 ml, and the resulting solution was used as a standard solution.

The dissolution test system is shown below.
Dissolution test device: DT-600 (manufactured by JASCO)
UV-Visible partial photometer: HP 8452A Diode-array UV-Visible Spectrophotometer (Hewlett Packard: current Agilent Technologies)
Cell positioner: HP 89075C Multicell Transport (manufactured by Hewlett Packard)
Pump: HP 89092A Multichannel Pump (manufactured by Hewlett Packard)
Dissolution testing software: Hewlett Packard Dissolution Testing Software, Revision 03.01 (manufactured by Hewlett Packard)
Analysis wavelength: 254 to 258 nm
Control wavelength: 322 to 326 nm
Integration time: 1 sec
Optical path length of quartz cell: 0.5 cm
(2) Results Table 4 shows the elution rate calculated from the concentration of compound (I) in the test solution measured in the above test using the compound of Example 1 and compound (I) as the test compound.

[Table 4]
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Test compound dissolution rate (%)
Number Time (minutes): 5 10 15 20 30 45
￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣
Example 1 1.0 1.9 3.3 5.0 9.9 23.5
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Compound (I) 0.5 0.7 1.0 1.3 1.8 2.5
￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣
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Test compound dissolution rate (%)
Number Time (minutes): 60 75 90 105 120
￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣
Example 1 35.5 40.8 45.1 49.6 52.6
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Compound (I) 3.1 3.6 4.1 4.5 5.0
￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣￣

Since the compound of Example 1 of the present invention showed superior dissolution properties compared to the free compound (I), it is considered to exhibit better oral absorption.

(Test Example 4) Calcium channel receptor binding test using rat cerebral cortex membrane fraction Rat cerebral cortex membrane fraction as a source of L-type calcium channel and ³ H-(+)-as a ligand of L-type calcium channel Isradipine was used. Membrane fraction (5.0 mg protein / ml), ³ H-(+)-isradipine (0.5 nM) and test compound in tris (hydroxymethyl) aminomethane hydrochloride (Tris-HCl; 50 mM, pH 7.4) buffer Was reacted at room temperature for 60 minutes, and ³ H-(+)-isradipine bound to the membrane fraction was measured with a liquid scintillation counter. The specific binding amount was calculated by subtracting the count in the presence of unlabeled nitrendipine (non-specific binding amount) from the measured count. For each test compound, the relationship between the specific binding concentration and the binding inhibition rate was applied to the logit-log model, and the IC ₅₀ value (specific binding 50% inhibitory concentration; nM) and Ki value (dissociation constant; nM) were calculated. did.

  The compounds of Examples 1 to 7 showed Ki values of 4.8 to 9.2 nM. The specific acid addition salt of the compound (I) of the present invention exhibits excellent calcium channel receptor antagonistic activity, and is useful as a medicament for the treatment or prevention of hypertension, heart disease, arteriosclerosis, or renal disorder. It is.

  Test Example 4 can also be performed using porcine myocardial microsomes as a source of L-type calcium channels.

(Test Example 5) Blood pressure lowering effect test in hypertensive rats Using male spontaneously hypertensive rats, the test compound was orally administered without anesthesia, and blood pressure was measured by telemetry every 5 minutes for 24 hours. Test compounds were suspended in 0.5% methylcellulose solution and administered to rats. From the rate of decrease in blood pressure at each measurement time point, the area from the time of administration to 24 hours after administration was calculated by the trapezoidal method, and the blood pressure decrease rate area value (% · hr) was determined.

  The compounds of Examples 1 to 7 exhibited a blood pressure lowering rate area value of 132 to 242 (% · hr). The specific acid addition salt of the compound (I) of the present invention exhibits an excellent blood pressure lowering action and is useful as a medicament for the treatment or prevention of hypertension and the like.

(Formulation Example 1) Capsules Example compound (10.0 mg), lactose (168.7 mg), corn starch (70.0 mg), and magnesium stearate (1.3 mg) (total 250 mg) powders are mixed to obtain 60 mesh Then, this powder is put into a No. 2 gelatin capsule to form a capsule.

(Formulation example 2) Tablet Powders of Example compound (10.0 mg), lactose (149.0 mg), corn starch (40.0 mg), and magnesium stearate (1.0 mg) (total 200 mg) were mixed and mixed with a tableting machine. Tablet into 1 tablet 200mg.

2-amino-1,4-dihydro-6-methyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 3- (1-diphenylmethylazetidin-3-yl) ester of the present invention 5- Certain acid addition salts of isopropyl ester have excellent calcium antagonism, blood pressure lowering action, vasodilatory action, cardioprotective action, anti-arteriosclerotic action, diuretic action, renal disorder inhibitory action, and lipid peroxide production inhibitory action. Physicochemical properties, thermal stability, storage and handling stability, residual solvent ratio, hygroscopicity, deliquescence, solubility, pharmacological properties, pharmacokinetic properties, oral absorption, blood Since it has excellent properties as a pharmaceutical compound in terms of concentration, bioavailability, pharmacokinetics, safety, and toxicity, it is preferably used as a medicament as a hypertension, heart disease, arteriosclerosis, or Useful as a medicament for the treatment or prevention of disorders, more preferably as a medicament for the treatment or prevention of hypertension or heart disease, most preferably as a medicament for the treatment or prevention of hypertension It is. In addition, the specific acid addition salt of the compound (I) of the present invention may have an excellent property that the blood concentration does not vary greatly due to changes in gastric pH and is not easily affected by food. As a blood animal medicine, it is preferably useful as a human medicine.

2-Amino-1,4-dihydro-6-methyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 3- (1-diphenylmethylazetidin-3-yl) obtained in Example 1 Ester 5-Isopropyl ester Hydroxyl bromide powder X-ray diffraction pattern. 2-Amino-1,4-dihydro-6-methyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 3- (1-diphenylmethylazetidin-3-yl) obtained in Example 3 Ester 5-Isopropyl ester Powder X-ray diffraction pattern of dimethanesulfonate. 2-Amino-1,4-dihydro-6-methyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 3- (1-diphenylmethylazetidin-3-yl) obtained in Example 4 Ester 5-Isopropyl ester Powder X-ray diffraction pattern of trimethanesulfonate. 2-Amino-1,4-dihydro-6-methyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 3- (1-diphenylmethylazetidin-3-yl) obtained in Example 6 Ester 5-Isopropyl ester Powder X-ray diffraction pattern of 2-p-toluenesulfonate. 2-Amino-1,4-dihydro-6-methyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 3- (1-diphenylmethylazetidin-3-yl) obtained in Example 2 X-ray powder diffraction pattern of ester 5-isopropyl ester monocitrate. 2-Amino-1,4-dihydro-6-methyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 3- (1-diphenylmethylazetidin-3-yl) obtained in Example 5 Ester 5-Isopropyl ester Powder X-ray diffraction pattern of dibenzenesulfonate. 2-Amino-1,4-dihydro-6-methyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 3- (1-diphenylmethylazetidin-3-yl) obtained in Example 7 Ester 5-Isopropyl ester Powder X-ray diffraction pattern of dinaphthalene sulfonate. 2-Amino-1,4-dihydro-6-methyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 3- (1-diphenylmethylazetidin-3-yl) obtained in Comparative Example 1 X-ray powder diffraction pattern of ester 5-isopropyl ester dihydrochloride. 2-amino-1,4-dihydro-6-methyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 3- (1-diphenylmethylazetidin-3-yl) obtained in Comparative Example 2 X-ray powder diffraction pattern of ester 5-isopropyl ester dihydrochloride. 2-amino-1,4-dihydro-6-methyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 3- (1-diphenylmethylazetidin-3-yl) obtained in Comparative Example 3 Ester 5-Isopropyl ester Monosulfate powder X-ray diffraction pattern. 2-amino-1,4-dihydro-6-methyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 3- (1-diphenylmethylazetidin-3-yl) obtained in Comparative Example 4 Ester 5-Isopropyl ester Powder X-ray diffraction pattern of 1/2 difumarate.

Claims (19)

2-amino-1,4-dihydro-6-methyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 3- (1-diphenylmethylazetidin-3-yl) ester 5-isopropyl ester A medicine containing hydrobromide, citrate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, or naphthalenesulfonate as an active ingredient.
The 2-amino-1,4-dihydro-6-methyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 3- (1-diphenylmethylazetidin-3-yl) ester in claim 1 A pharmaceutical comprising 5-isopropyl ester hydrobromide, methanesulfonate, or p-toluenesulfonate as an active ingredient.
The 2-amino-1,4-dihydro-6-methyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 3- (1-diphenylmethylazetidin-3-yl) ester according to claim 2 A medicament comprising 5-isopropyl ester hydrobromide as an active ingredient.
The 2-amino-1,4-dihydro-6-methyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 3- (1-diphenylmethylazetidin-3-yl) ester in claim 3 A medicament comprising 5-isopropyl ester dihydrobromide as an active ingredient.
In Claim 4, 2-amino-1,4-dihydro-6-methyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 3- (1-diphenylmethylazetidin-3-yl) ester A medicament comprising crystals of 5-isobromide dihydrobromide as an active ingredient.
6. In the powder X-ray diffraction pattern obtained by irradiation with copper Kα rays in claim 5, the main spacing is 16, 4.4, 3.9, 3.1, and 3.0 angstroms. A medicine containing crystals as an active ingredient.
The 2-amino-1,4-dihydro-6-methyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 3- (1-diphenylmethylazetidin-3-yl) ester according to claim 2 A medicine containing methanesulfonate of 5-isopropyl ester as an active ingredient.
The 2-amino-1,4-dihydro-6-methyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 3- (1-diphenylmethylazetidin-3-yl) ester in claim 7 A medicament comprising dimethanesulfonate of 5-isopropyl ester as an active ingredient.
9. 2-Amino-1,4-dihydro-6-methyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 3- (1-diphenylmethylazetidin-3-yl) ester in claim 8 A pharmaceutical comprising a crystal of dimethanesulfonate of 5-isopropyl ester as an active ingredient.
In claim 9, the powder X-ray diffraction pattern obtained by irradiation with copper Kα rays shows major peaks at an interplanar spacing of 12, 7.8, 6.1, 4.8, and 4.5 angstroms. A medicine containing crystals as an active ingredient.
The 2-amino-1,4-dihydro-6-methyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 3- (1-diphenylmethylazetidin-3-yl) ester in claim 7 A medicament comprising trimethane sulfonate of 5-isopropyl ester as an active ingredient.
The 2-amino-1,4-dihydro-6-methyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 3- (1-diphenylmethylazetidin-3-yl) ester according to claim 11. A medicament comprising crystals of 5-isopropyl ester trimethanesulfonate as an active ingredient.
In claim 12, in the powder X-ray diffraction pattern obtained by irradiation with copper Kα rays, the major distance peaks are 11, 4.6, 4.4, 3.9, and 3.6 angstroms. A medicine containing crystals as an active ingredient.
The 2-amino-1,4-dihydro-6-methyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 3- (1-diphenylmethylazetidin-3-yl) ester according to claim 2 A medicament comprising p-toluenesulfonate of 5-isopropyl ester as an active ingredient.
15. A 2-amino-1,4-dihydro-6-methyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 3- (1-diphenylmethylazetidin-3-yl) ester according to claim 14. A medicament comprising 2-p-toluenesulfonate of 5-isopropyl ester as an active ingredient.
The 2-amino-1,4-dihydro-6-methyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 3- (1-diphenylmethylazetidin-3-yl) ester in claim 15 A medicament comprising crystals of 2-p-toluenesulfonate of 5-isopropyl ester as an active ingredient.
In the powder X-ray diffraction pattern obtained by irradiation with copper Kα rays in claim 16, crystals having major peaks at interplanar spacings of 6.8, 4.9, 4.7, and 4.2 angstroms are obtained. A medicine containing as an active ingredient.
18. The medicament for treating or preventing hypertension, heart disease, arteriosclerosis, or renal disorder according to any one of claims 1 to 17.
  19. The medicament for treating or preventing hypertension according to claim 18.